The present invention relates to a series of novel substituted 5-alkynyl pyrimidines, to pharmaceutical compositions which contain them, to methods for their preparation and to their use in therapy, particularly in the treatment of neurodegenerative or other neurological disorders of the central and peripheral nervous systems including age related cognitive disorders such as senility and Alzheimer's disease, nerve injuries, peripheral neuropathies, and seizure disorders such as epilepsy.
Dementing disorders such as age-related cognitive disorders, e.g., senility or Alzheimer's disease are medical conditions for which there are currently only limited therapies. Although studies suggest that multiple neurotransmitter systems are involved in senile dementia, a loss of cholinergic neurons and a severe depletion of choline acetyltransferase appear to show the earliest and strongest correlation with functional cognitive impairment [see P. T. Francis et al., Neurochemical Studies of Early-onset Alzheimer's Disease. N. Engl. J. Med., 313, 7 (1985); R. T. Bartus et al., The Cholinergic Hypothesis: A Historical Overview, Current Perspective, and Future Directions. Ann. N. Y. Acad. Sci., 444, 332 (1985); F. Hefti and L. S. Schneider, Nerve Growth Factor and Alzheimer's Disease, Clin. Neuropharmacol., 14, S62 (1991)]. Several groups have attempted to stimulate cholinergic activity by blocking the breakdown of acetylcholine with acetylcholine esterase inhibitors or by introducing muscarinic or nicotinic agonists [see R. T. Bartus et al., The Cholinergic Hypothesis of Geriatric Memory Dysfunction. Science, 217, 408 (1982); J. Varghese et al., Chapter 21. Alzheimer's Disease: Current Therapeutic Approaches. Annu. Rep. Med. Chem., 28, 197 (1993)]. The approved drugs COGNEX and ARICEPT are acetylcholine esterase inhibitors.
Nerve growth factor (NGF) is the best characterized neurotrophic factor that is capable of inducing cell differentiation of neural cells and promoting neurite sprouting. The neurotrophic protein NGF primarily affects cholinergic neurons in the central nervous system and may be necessary for their survival [see F. Hefti and P. A. Lapchak, Pharmacology of Nerve Growth Factor in the Brain. Adv. Pharmacol., 24, 239 (1993)]. NGF is not systemically bioavailable, but if it is injected or infused directly into brain, it prevents neuronal cell loss and restores cognitive function in aged or lesioned rats or monkeys [see W. Fischer et al., NGF Improves Spatial Memory in Aged Rodents as a Function of Age. J. Neurosci., 11, 1889 (1991)]. NGF effects ultimately result in the stimulation of choline acetyltransferase, the enzyme for biosynthesis of acetylcholine and the promotion of neurite growth. Consequently, small molecules that produce neurotrophic or “nerve growth factor-like” (NGF-like) properties in mammalian cell cultures have potential for use in the treatment of dementing disorders such as age-related senility or Alzheimer's disease and other neurodegenerative conditions such as peripheral neuropathies, Parkinson's, stroke damage, transient ischemic attacks, trauma-head injuries or other nerve injuries.
Since pancreatic cells producing insulin synthesize, secrete and are stimulated by nerve growth factor, another potential use of the compounds of the present invention is in the treatment of diabetes. [See T. Rosenbaum et al., Pancreatic B Cells Synthesize and Secrete Nerve Growth Factor, Proc. Natl. Acad. Sci. USA, 95, 7784 (1998)].
There are several reports of small molecules that exhibit various aspects of NGF-like activity. Isaxonine [2-(isopropylamino)pyrimidine] was developed as a neurotrophic pharmaceutical but the clinical application was withdrawn, possibly due to toxicological effects [see S. Lehmann et al., Neurite Outgrowth of Neurons of Rat Dorsal Root Ganglia Induced by New Neurotrophic Substances with Guanidine Group. Neurosci. Lett., 152, 57 (1993)]. Several 2-(piperazino)pyrimidine derivatives were reported to possess NGF-like activity and are being studied further for use in treating CNS degenerative diseases [see A. Awaya et al., Neurotrophic Pyrimidine Heterocyclic Compounds. Biol. Pharm. Bull., 16, 248 (1993)]. AIT-082 (4[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]benzoic acid) is reported to enhance NGF action in cultured PC-12 cells and to restore age-induced working memory deficits in mice [see P. J. Middlemiss et. al., AIT-082, A Unique Purine Derivative, Enhances Nerve Growth Factor Mediated Neurite Outgrowth from PC-12 cells. Neuroscience Let., 199, 131 (1995)]. The compound SR57746A is reported to have nerve growth factor potentiating activity and is in clinical trials [see Fournier J, et al. Protective Effects of SR57746A in Central and Peripheral Models of Neurodegenerative Disorders in Rodents and Primates. Neuroscience, 55(3), 629–41, August 1993; U.S. Pat. Nos. 5,270,320 and 5,462,945]. The compound BW 394U, 2-amino-5-(4-chlorophenyl)thio-4-morpholinopyrimidine, is described as a potential antisenility agent [see Samano et. al., J. Heterocyclic Chem., 37, 183 (2000)]. In addition, WO98/12190, WO99/19305, WO00/59893, WO00/61562, EP0372934, EP0459819 and U.S. Pat. No. 5,075,305 disclose substituted pyrimidines having NGF-like activity and their possible use in treating CNS degenerative diseases like Alzheimer's disease as well as peripheral neuropathies and other disorders of the central and peripheral nervous system. WO94/14780 discloses certain structurally similar pyrimidine derivatives as neuronal nitric oxide synthase inhibitors.